This invention relates to newly identified polypeptides and polynucleotides encoding such polypeptides, to their use in identifying compounds that may be agonists and/or antagonists that are potentially useful in therapy, and to production of such polypeptides and polynucleotides.
The drug discovery process is currently undergoing a fundamental revolution as it embraces xe2x80x98functional genomicsxe2x80x99, that is, high throughput genome- or gene-based biology. This approach is rapidly superseding earlier approaches based on xe2x80x98positional cloningxe2x80x99. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position.
Functional genomics relies heavily on the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and characterise further genes and their related polypeptides/proteins, as targets for drug discovery.
Multi-specific drug transporters are present in cells having a barrier function such as intestinal epithelial and brain microvessel endothelial cells. Other tissues, for example, liver and kidney, also contain multi-specific transporters that can mediate the excretion of drugs and metabolites. Information gained from using multi-specific transporters such as the mouse OATP5 gene product in cell based, membrane-based, binding or other assays could enhance drug formulation, selection of formulation excipients, and compound design.
The present invention further relates to methods for creating transgenic animals, which overexpress or underexpress or have regulatable expression of a mouse OATP5 gene and xe2x80x9cknock-outxe2x80x9d animals, preferably mice, in which an animal no longer expresses a mouse OATP5 gene. Furthermore, this invention relates to transgenic and knock-out animals obtained by using these methods. Such animal models are expected to provide valuable insight into the potential pharmacological and toxicological effects in humans of compounds that are discovered by the aforementioned screening methods as well as other methods. An understanding of how a mouse OATP5 gene functions in these animal models is expected to provide an insight into treating and preventing human diseases including, but not limited to cancer, inflammation, cardiovascular disease, central nervous system disorders, auto-immune disease, and kidney and liver disease, hereinafter referred to as xe2x80x9cthe Diseasesxe2x80x9d, among others.
In a further aspect, the invention relates to methods for identifying agonists and antagonists/inhibitors using the materials provided by the invention, and treating conditions associated with OATP5 imbalance in humans with the identified compounds. Another embodiment of this invention provides for methods to identify compounds that neither agonise nor antagonise OATP5. This invention further relates to the generation of in vitro and in vivo comparison data to predict oral absorption and pharmacokinetics in man. Such a comparison of data will enable selection of drugs with optimal pharmacokinetics in man, i.e., good oral bioavailability, brain penetration, plasma half life, and minimum drug interaction.